Renewal of support beyond the present project period of grant NS 09931-04 is requested for five years to continue experimental and theoretical studies on the selective ion permeation through lipid bilayer membranes mediated by carriers and channels, with the broad objective of understanding, at a molecular level, the selectivity and permeation mechanisms of nerve. Two main approaches are proposed. 1. experimental and theoretical studies of well defined carriers and channels which have been reconstituted in vitro in bilayer membranes from molecular components (e.g. polypeptides) of the type thought to be present in nerve membranes. These studies are directed toward ascertaining the essential similarities and differences between carriers and channels in their bioelectrical properties. 2. experimental and theoretical studies of the influence on ion selectivity of the molecular structure of the binding site (as well as of the electronic and molecular structure of the bound ion). These studies should extend the basis already laid by Hille and Armstrong, for using ions as "probes" of the structure of the Na ion and K ion channels of nerve, since it is possible in artificial systems to study systematically variation in the cavity size and ligand "field strength" of a selected carrier molecules and channels. Our approach encompasses the extension of theoretical considerations to include the effects of rate-limiting steps in the formation of the complexes, their rate of crossing the membrane-solution interface, and the effects of the charge of the polar head groups, as well as extensions to channels.